Abstract 4544: Novel indolequinone inhibitors of thioredoxin reductase are active against human pancreatic cancer

Abstract

Abstract A series of indolequinones was previously developed in our lab as potential antitumor agents against pancreatic cancer. Three general classes of indolequinone consisting of 2-methyl, 2-hydroxymethyl and 2-unsubstituted derivatives with varying leaving groups at the indole 3- position exhibited marked activity against human pancreatic cancer both in vitro and in vivo. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used to ensure effects were not cell line specific and growth inhibitory effects were measured using both the MTT and clonogenic assays. Indolequinones displayed growth inhibitory activity against pancreatic tumor cells in vitro and two specific classes of indolequinone, the 2-unsubstituted and 2-hydroxymethyl classes, were particularly active agents with IC50 values in the 20-200nM range. Indolequinones were also found to be efficient inducers of apoptosis in pancreatic cancer cell lines at concentrations which induced growth inhibition. Selected indolequinones were also screened against the NCI-60 cell line panel to reveal the pattern of activity across various tumor types and were particularly effective against colon, renal, and melanoma cancer cells. The spectrum of activity of indolequinones in the NCI-60 was similar to established inhibitors of thioredoxin reductase. Indolequinones of both the 2-hydroxymethyl and 2-unsubstituted classes were found to inhibit thioredoxin reductase in MIA PaCa-2 cellspancreatic cancer at concentrations equivalent to those inducing growth inhibitory effects. The mechanism of inhibition of thioredoxin reductase by the indolequinones was studied in detail in cell-free systems using purified enzyme and the C-terminal selenocysteine of thioredoxin reductase was found to be the primary adduction site of the indolequinones using LC-MS analysis. Inhibition of thioredoxin reductase by indolequinones in cells resulted in a change of thioredoxin redox state and activation of the P38/JNK signaling pathway which may result in downstream apoptosis. Our results demonstrate that thioredoxin reductase is a potential target of the indolequinones in pancreatic cancer cells. (Supported by CA11441). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4544.